Age-related macular degeneration (AMD) is recognized as the leading cause of blindness in the United States. It affects nearly 1.5 million older Americans and causes loss of vision in more than 7 percent of individuals over 75 years of age. Currently, there are no established means of preventing AMD. The only proven effective treatment, laser photocoagulation, is successful in only a small proportion of cases. While the etiology of AMD is unknown, there is considerable evidence implicating a strong genetic component for the disease. Advances in genomic screening and analysis methodologies make a direct genetic approach to the etiology, pathophysiology, and ultimate therapy of AMD viable. Recent successes with other complex traits, which share genetic and epidemiological similarities with AMD, support the idea that identification of genetic loci responsible for AMD is an achievable goal. The long-term objectives of this project are to identify genes responsible for AMD, develop diagnostic tools to identify patients at risk of developing the disease, and to understand its molecular pathophysiology. This understanding will allow the development of preventive measures and improved methods of treatment. The immediate goal of this research proposal is to map genetic loci cosegregating with AMD in a number of affected families. We will employ both parametric and several nonparametric linkage analysis methods. To achieve these goals, we propose to: 1) Continue to collect additional kindreds containing multiple affected living members; 2) Complete genome-wide screening of AMD families, beginning with a set of candidate loci; 3) Fine-map loci suggestive of linkage and conduct detailed multi- point parametric and nonparametric linkage analysis; and 4) Refine identified loci and begin studies to identify the specific genetic defects responsible for AMD in these families.